The present invention relates to non-natural galanin receptor ligands which can function as agonists and antagonists of galanin and can be used to treat diseases or conditions in which galanin plays a role.
Galanin1 is a 29/30 amino acid long neuroendocrine peptide that potently affects seizure activity, cognition, mood, feeding, and pain threshold2-6. Galanin-overexpressing mice have increased resistance to status epilepticus, while galanin knockout mice have lowered seizure threshold6. These results indicate that endogenous galanin is an important determinant of hippocampal excitability and of seizure threshold. The importance of galanin agonists for seizure control may arise from their ability to act at both pre- and postsynaptic sites to reduce excitability, to inhibit glutamate but not GABA release7, and to hyperpolarize both dentate granule cells and CA1-CA3 pyramidal cells by opening K+-channels8, dampening seizure activity. Although intracerebroventricularly injected galanin blocks seizures5 in mice, this large peptide is unable to cross the blood-brain barrier and is rapidly degraded.
To date, there are only two reports on non-peptide ligands for galanin receptors, which behave as antagonists: spirocoumaranon9 (Sch 202596; IC50 of 1.4 xcexcM at human GalR1) and dithiipin-1,1,4,4-tetroxide10(IC50 of 0.17 xcexcM at human GalR1), despite extensive random screening efforts at six large pharmaceutical companies.
In accordance with the present invention, there are provided low molecular weight ligands for galanin receptor(s) having the formula: 
wherein:
R1, R1xe2x80x2, and R1xe2x80x3 are each independently hydrogen or lower alkyl,
R2 and R2xe2x80x2 are each independently an optionally substituted hydrocarbyl moiety containing at least about four carbon atoms,
E is optional, and, if present, is O, N or S,
X is a hydrocarbyl moiety bearing at least one substituent, wherein at least one of said substituents bears a positive charge,
Ar is an optionally substituted aromatic or heteroaromatic moiety having at least about three carbon atoms, and
n is 1, 2 or 3.
A preferred embodiment of the above compounds has been given the name xe2x80x9cgalnonxe2x80x9d: Fmoc-Cha-Lys-amidomethyl coumarin (according to IUPAC systematic nomenclature: 1-[5-amino-1-(4-methyl-2-oxo-2H-chromen-7-ylcarbamoyl)-pentylcarbamoyl]-2-cyclohexyl-ethyl-carbamic acid 9H-fluoren-9-ylmethyl ester).
The galanin receptor ligands of the invention are characterized in having galanin agonist or antagonist activity, are generally 700 daltons or less in molecular weight, and have the ability to cross the blood-brain barrier.
Also provided herein are various uses for the invention ligands, including in vitro and in vivo analysis of galanin receptor structure and function, and use in treating a variety of diseases and conditions in which galanin plays a role. Such diseases or conditions include convulsions such as in epilepsy, growth, diabetes, pain, allodynia psychiatric states, cognition, and feeding. For such uses, the invention compounds can be formulated with an appropriate excipient(s) for pharmaceutical administration to a mammalian patient.
These and other aspects of the invention will be addressed in greater detail below.